Using resting-state functional alcoholic narcissistic mother MRI (fMRI), Liao al. investigated the functional connectivity between the thalamus and specific cortical regions in 40 chronic ketamine users with a mean use of 2 grams/day for 3.4 years, compared to 88 drug-free controls (Liao et al., 2016). Lower functional connectivity was found between the thalamus and the motor-, posterior parietal- and prefrontal cortex. Functional connectivity between the posterior parietal cortex and right lateral dorsal nucleus was significantly correlated to individual ketamine craving scores (Liao et al., 2016). ReHo describes the summarized local functional connectivity between a voxel and its neighboring voxels. This is an index of network centrality, showing the importance of a voxel in a functional network. In 41 chronic ketamine users with a mean use of 2 grams/day for 3.4 years compared to 44 drug-free controls, lower ReHo in the right anterior cingulate cortex and higher ReHo in the left precentral frontal gyrus were found (Liao et al., 2012).
It remains unclear, though, if repeated infusions of ketamine will increase propensity for ketamine abuse or relapse to other addictive drugs following antidepressant treatment. To answer this, studies examining the effects of slow, low-dose ketamine infusions on subsequent ketamine self-administration are necessary. Studies examining the antidepressant effects of repeated (R)-ketamine infusions across different doses are also necessary to potentially reduce risk for abuse and cognitive deficits. Li et al. (2017) assessed resting-state functional connectivity of the subgenual anterior cingulate cortex (sgACC) in relation to depression scores of 36 chronic ketamine users with an average ketamine use of 4.9 years (dose not reported) compared to 20 drug-free controls. Overall, no difference in sgACC connectivity was found between groups, but in ketamine users higher depression scores correlated with lower sgACC connectivity to the right lateral and bilateral medial OFC. Further analysis revealed functional connectivity changes, with male and female ketamine users showing higher sgACC connectivity than controls to the bilateral superior temporal gyrus or dorsomedial prefrontal cortex (dmPFC), respectively (Li et al., 2017).
If true, this process would predict the observation of hallucinations in ketamine under conditions of sparse sensory input as described here. This 21-year-old female graduate student in robotics volunteered and qualified for our research study. When the infusion began and her first blood sample was drawn (for plasma ketamine assay), she became concerned that something had gone awry with the experiment. She reported thinking more solution focused therapy interventions about life and its purpose and that her philosophy was “somewhere between Dr. Who and the Matrix” (she had been watching Dr. Who the day before).
1. Clinical evidence
Repeated administration of ketamine, which is necessary to sustain an antidepressant response in humans, may have an abuse potential. Ketamine, like most drugs of abuse, can induce sensitization to its locomotor activating effects. In both sexes of rats, daily administration of ketamine induces sensitization to its locomotor-activating effects (Table 1) (Botanas et al., 2015; Wiley et al., 2011). Intermittent, every other day administration of ketamine induced locomotor sensitization in both sexes, but females were more sensitive as locomotor sensitization occurred at lower doses (2.5 mg/kg, i.p.) when compared to males (5 mg/kg, i.p.) (Schoepfer et al., 2017).
This treatment regimen not only impairs memory but also induces a delayed onset of aberrant social behavior in juvenile mice. In the social interaction test, repeated exposure to ketamine (20 mg/kg, i.p.) during adolescence, from PND weeks 4–7, did not alter any measures of social interaction in juvenile mice, but social interaction was disturbed when mice became adults (Nagy et al., 2015). Interestingly, patients with a family history of alcoholism report no instances of dissociative symptoms when receiving low-dose ketamine (0.5 mg/kg, i.v.) infusions (Fig. 1) (Petrakis et al., 2004). In fact, subjects with a family history of alcoholism are less sensitive to the effects of the NMDAR-antagonist, memantine, likely because of increased NMDAR-function (Jamadar et al., 2012).
Subjects
In addition to alleviating symptoms and boosting neurobiological learning processes, this approach seems to aid patients by promoting early involvement in cognitive-behavioral therapy (CBT). This therapeutic combination of ketamine and CBT may result in better long-term results while reducing the requirement for continued ketamine exposure 14,15. In addition, early data suggests that ketamine might enhance negative self-schemas, which is one of the primary therapy goals of CBT 16. Hospitalization can be an essential part of a person’s treatment and recovery from a drug-induced episode of psychosis or an exacerbation (worsening) of schizophrenia. Studies show that up to one in four people hospitalized with psychosis for the first time have substance-induced symptoms. This condition typically begins as substance-induced psychosis, which is a break from reality following taking or withdrawing from a substance.
- Using diffusion-weighted MRI scans, fractional anisotropy (FA) can be used for estimating white matter fiber density, myelination and axonal diameter.
- Additionally, they must exhibit one or more other symptoms that can also include catatonic behavior or a flat affect.
- “Additionally, by illustrating the roles of these brain nodes and networks involved in mediating dissociative states, we may develop improved insights — and possible treatments for — certain types of drug-induced psychoses, and perhaps other psychotic conditions, such as forms of schizophrenia, as well,” he concluded.
Subjects were screened using an initial telephone interview and subsequent personal interview. Psychiatric or physical illness, head injury, drug or alcohol dependence, and smoking were excluding factors, as duloxetine and alcohol were family history of psychiatric illness and alcohol problems. Participants in this series reported auditory verbal and musical hallucinations at a ketamine dose that does not induce auditory hallucination outside of the scanner. “It may be, for example, that the effects produced by ketamine in humans, while certainly being dissociative, and having certain characteristics of psychosis, are not completely representative or identical to the neurological mechanisms involved in other types of psychosis and schizophreniform disorders,” Dr. Giordano further noted.
Ketamine users also showed a higher connectivity between the pallidum and the bilateral cerebellum. Furthermore, in ketamine users, the putamen showed higher connectivity to the OFC, which correlated with duration of ketamine use. Also, the ventral striatum (VS) showed lower connectivity with the right superior temporal sulcus (STS) and the left superior frontal gyrus (SFG) which was mediated by higher scores on the Barratt Impulsiveness Scale (BIS-11) (Hung et al., 2020b). Lin et al. used resting state fMRI to compare a group of chronic ketamine users, many of which also used other drugs like cannabis or cocaine, to healthy controls (Liu et al., 2016).
Symptoms
With the onset of rapid-acting ADT (RAAD), a high proportion of patients who have been considered treatment-resistant and difficult to treat may benefit from a novel pharmacological approach for mood disorders. Studies examining ketamine self-administration at low doses have not yet examined the molecular mechanisms underlying ketamine’s reinforcing effects. These molecular changes induce a hyperexcitable state in the NAc, which is also observed following chronic exposure to other drugs of abuse such as alcohol, another NMDAR-antagonist (Ron and Barak, 2016). It is therefore important to examine whether these molecular changes will also occur at therapeutic low doses of ketamine, and it is particularly important to further delve into the molecular mechanisms mediating the reinforcing properties of chronic exposure to low-dose ketamine as a treatment for depression. The included studies followed a cross-sectional and retrospective design with considerable variability among studies in terms of subject age, ketamine type and dosage. It should be noted that in some studies, ketamine users had a mood disorder and for many of the studies it was unclear whether the ketamine users were diagnosed with another substance use disorder or another psychiatric illness.
These symptoms must persist most of the time for at least one month, at levels that interfere with work, relationships, and other features of daily life.
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